Project Summary The COVID-19 pandemic has affected millions worldwide, however it is clear that there are predisposing factors that lead to critical illness and mortality including older age, and underlying conditions particularly type 2 diabetes (T2DM) and obesity. The Centers for Disease Control and Prevention (CDC) has reported that patients with T2DM may have up to ten-times greater risk of death when they contract COVID-19. Understanding the immune response is critical to preventing or reducing mortality from COVID-19 and informing therapeutic strategies for this patient population. The overall aim of this proposal is to identify the immune basis for increased disease severity and death from COVID-19 in patients with obesity and T2DM. It is now appreciated that obesity is associated with immune dysregulation, which may be the cause of some obesity related diseases. For example, Natural killer (NK) cells, so-called due to their natural cytotoxicity against viruses and tumors, are unable to kill targets efficiently in obese humans and mice. We have recently found similar defects in CD8 T cells in patients with obesity and T2DM. The key unanswered questions are 1) are these immune defects responsible for the increased severity and death from COVID-19 in patients with obesity and T2DM 2) do patents with obesity and T2DM have an underactive or overactive (damaging cytokine storm) in response to COVID-19? and 3) is metabolic dysregulation at the heart of these defects? It is critical to understand the immune basis for this susceptibility in order to prevent or reduce mortality from COVID-19 and to inform therapeutic strategies in this patient populations. Findings from this study may lead to understanding the immune response in patients with obesity for future novel viral outbreaks.